Results suggest less frequent dosing provides same benefit while reducing cost and potential side effects

New research at Christiana Care has the potential to reduce medication side effects and health care costs for certain groups of cancer patients.

Researchers at the Helen F. Graham Cancer Center & Research Institute at Christiana Care conducted a randomized clinical trial to determine if administration of zoledronic acid over longer dosing intervals of every 12 weeks instead of the standard every four weeks over two years were equivalent. Their conclusions show that among patients with bone metastases due to breast cancer, prostate cancer or multiple myeloma, the longer dosing interval may be an acceptable treatment option.

The team of researchers led by Andrew L. Himelstein, M.D., medical oncologist at the Helen F. Graham Cancer Center & Research Institute, published its findings in the Jan. 3 issue of the Journal of American Medical Association (JAMA). Louise Brady, RN, BSN, OCN, research nurse coordinator, served as nurse liaison for all trial participants.

The U.S. Food and Drug Administration (FDA) approved zoledronic acid for the treatment of bone metastases in patients with multiple myeloma and solid tumors in 2002. The authors note that studies show zoledronic acid reduces pain and the incidence of skeletal-related events — complications associated with bone metastases, including fractures, spinal cord compression and the need for surgery or radiation therapy to bone — by approximately 25 to 40 percent.

Zoledronic acid is in the bisphosphonate class of drugs. It has the brand name Zometa and is manufactured by Novartis. Bisphosphonates are used to slow down or prevent bone damage. And, although bisphosphonates are generally well tolerated, associated side effects include osteonecrosis of the jaw (damage to the jawbone), nephrotoxicity (kidney damage), and hypocalcemia (low levels of calcium in the blood). The authors describe that the risk for osteonecrosis of the jaw increases with cumulative drug exposure.

“Our results showed no increase in the risk of skeletal-related events (namely, clinical fractures, spinal cord compression, radiation to bone, or surgery to bone) or in the risk of side effects when zoledronic acid was administered every 12 weeks instead of the standard interval of every four weeks for two years in patients with bone metastases from breast cancer, prostate cancer, or multiple myeloma,” said Dr. Himelstein.

The published study, titled “Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases, A Randomized Clinical Trial,” describes how the efficacy of the new dosing intervals of zoledronic acid is equivalent to the standard dosing intervals. The implication is that patients can receive fewer doses of zoledronic acid over a two-year period, with the same results.

The trial was conducted at 269 academic and community sites in the United States. A total of 1,822 patients who had at least one site of bone involvement (855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma) were enrolled in the trial between May 2009 and April 2012, and 795 patients completed the study at two years. Follow-up concluded in April 2014. The Graham Cancer Center was one of highest enrollers in the trial with more than 80 patients participating.

Results show that a total of 260 patients (29.5 percent) in the four-week dosing group and 253 patients (28.6 percent) in the 12-week dosing group experienced at least one skeletal-related event within two years of randomization. The difference between the two dosing groups was well below the set 7 percent non-inferiority margin, implying that the less frequent dosing of zoledronic acid over two years had the same effect as the standard dosing interval.

Secondary objectives of the study were to determine if lowering the number of zoledronic acid doses from every four weeks to every 12 weeks, over a two-year period, would increase the number of skeletal events per year by cancer type, amount of pain and performance status, and incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity, and suppression of bone turnover.

Results demonstrated that the mean number of skeletal-related events per year was 0.4 for both groups. Pain and performance status scores also were similar between the two groups. Osteonecrosis of the jaw occurred in 18 patients (2 percent) in the group taking the drug every four weeks and in nine patients (1 percent) in the group taking the drug every 12 weeks. In addition, adherence to the treatment schedule was better among patients who took the drug every 12 weeks. For these patients, 63 percent had no treatment delays, compared with 38 percent of the group taking the drug every four weeks. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater among patients who received zoledronic acid every 12 weeks.

“We feel that patients with bone involvement from breast cancer, prostate cancer or multiple myeloma now have another option, namely to receive zoledronic acid every 12 weeks,” said Dr. Himelstein. The longer dosing interval may mean fewer trips to the hematologist’s or oncologist’s office, fewer intravenous treatments and lower cost without losing effectiveness.”